Autoimmune diseases develop when the immune system misidentifies a self-antigen as a foreign antigen and produces destructive responses to the self-antigen.
Patients with autoimmune disease frequently develop kidney involvement and/or lung malfunction. Identification of the potential for such organ involvement is clinically important so that these patients can be treated differently.
Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD) are chronic autoimmune diseases that target overlapping auto-antigens and exhibit similar clinical manifestations.
Previous studies have confirmed that components of the U1 small nuclear ribonucleoprotein complex (snRNP) such as U1A are 1000-fold more autoantigenic than any other nuclear component in SLE patients. The small nuclear RNP A (referred to here as “U1Ap”), in combination with U1-70K and U1C, is a specific U1 RNP peptide that, along with the U1-RNA and Smith (Sm) proteins, forms an active U1 snRNP complex. This complex, in turn, plays an essential role in pre-mRNA processing as a functional unit of the spliceosome. The U1Ap is composed of two RNA recognition motifs (RRM) located at the N- and C-tellninal of this spliceosomal protein and has been reported to be conserved across the eukaryote domain.
The N-terminal RRM domain 1 (RRM1) of U1Ap has been extensively studied and has been shown to be necessary and sufficient to bind U1-RNA via its stem loop II and facilitate the splicing process. In contrast, little is known about the potential function of U1Ap C-terminal RRM domain 2 (RRM2) despite similar characteristics to other RNA binding domains including U1Ap RRM1. U1Ap RRM2 exhibits unusual RNA binding properties because it does not bind to U1, U2, or U5 stem loops or interact with random RNA sequences.
Autoimmune responses to U1 snRNP specific proteins, including U1Ap, have been described in patients diagnosed with SLE and MCTD. In some cohorts, anti-U1Ap responses have been reported to be the first anti-U1-snRNP to develop.
Clinically, kidney damage is more frequent in SLE while lung malfunction is often observed in MCTD patients.
Previous studies have described elevated IgG autoimmune response to U1Ap fragments in both SLE and MCTD patients. In addition, SLE but not MCTD patients show a predominant immunoglobulin M (IgM) response to snRNP subunits, including U1Ap. Interestingly, while the immune response for U1A and U1 snRNP peptides mature from IgM to IgG in MCTD patients, SLE patients appear to retain IgM responses for these auto-antigens.